Polymeric matrix particle compositions containing coacervate polymer shell

ABSTRACT

This invention relates to the encapsulation of active ingredient within polymeric material so as to protect the active ingredient from the ambient environment, for instance atmospheric moisture when the product is exposed to the air, or the liquid phase of a liquid detergent when the product is incorporated in such a detergent. A dispersion in oil of an aqueous solution of a matrix polymeric material containing enzyme or other active ingredient is subjected to distillation to provide a substantially anhydrous dispersion in oil of particles of matrix polymer containing active ingredient, and during or after the distillation the polymer solution is converted into a solid polymer. In the invention, we use a matrix polymer that is so hydrophobic that it partitions preferentially into the oil rather than into the aqueous solution of encapsulating polymer. Because the aqueous solution is incompatible with both the hydrophobic oil and the matrix polymer, there is increased tendency for the encapsulating shell to be formed around a layer of oil, rather than in direct contact with a matrix polymer particle.

This application is a 371 of PCT application PCT/GB92/00867, filed May,14, 1992 and a continuation-in-part of U.S. Ser. No. 734,545 filed 23rdJul. 1991 by John Langley and Kenneth Symes (now U.S. Pat. No.5,324,445) and a C-I-P of U.S. application Ser. No. 398,083 filed 24thAug. 1989 by John Langley and Kenneth Symes (abandoned).

This invention relates to the encapsulation of active ingredient(especially detergent enzyme) within polymeric material so as to protectthe active ingredient from the ambient environment, for instanceatmospheric moisture when the product is exposed to the air, or theliquid phase of a liquid detergent when the product is incorporated insuch a detergent.

Numerous ways of protecting active ingredient from the ambientenvironment are known. Some rely on a wholly liquid system. In U.S. Pat.No. 4,801,544, aqueous micelles of enzyme and surfactant are emulsifiedinto a hydrocarbon solvent. In U.S. Pat. No. 4,906,396, enzyme isdispersed in a hydrophobic fluid, such as a silicone oil.

More usually, the enzyme is protected by a solid phase. In U.S. Pat. No.4,090,973, solid surfactant is used. Often, however, a polymericmaterial is used. The enzyme or active ingredient may be dispersed in apolymeric matrix or it may be encapsulated by a polymeric shell formedaround a core containing the active ingredient.

The solid polymeric material can be made by polymerisation of monomericmaterial in the presence of the active ingredient, but this is generallyundesirable and normally the solid polymer of the matrix or shell isformed by depositing solid polymer from a solution of polymer. Thepolymer can remain chemically unchanged during the deposition fromdissolved to solid form, the deposition being due primarily to a changein the solvent composition or properties. Alternatively, deposition canbe caused by, accompanied by or followed by a chemical change in thepolymer, such as neutralisation, complexing with another polymer, orcross linking. The formation of a solid polymer shell in this mannerfrom a solution of polymeric material is generally termed coacervation.

Typical techniques for forming a polymer shell are described in, forinstance, GB 1,275,712, 1,475,229 and 1,507,739, DE 3,545,803 and U.S.Pat. No. 3,591,090.

A particular problem arises when the active ingredient is an enzyme,especially an enzyme suitable for incorporation in detergents, becauseof the difficulty of preventing the enzyme losing activity before use.

Many different ways of encapsulating enzymes have been proposed. Some donot include coacervation. For instance GB 1,377,725 contacts atomiseddroplets of an aqueous slurry of enzyme with particles of starch.However there is a risk that the resultant coating will bediscontinuous. It is therefore preferred to form the coating or matrixby deposition of solid polymer from a solution of polymer in which theenzyme is dispersed, i.e. by coacervation.

For instance in U.S. Pat. No. 3,838,007 droplets of enzyme dispersed inan aqueous solution of, for instance, gelatin are dispersed into waterand then cross linked, to give cross linked particles of the gelatincontaining the enzyme.

In JP-A-61254244, a typical process comprises mixing enzyme powder andsilica into an aqueous solution of polyvinyl alcohol or other suitablepolymer, dispersing the aqueous suspension into a non-aqueous liquid andadding acetone, so as to deposit the polymer as a wall around the enzymeparticles. The product is said to have a particle size of around 50 to2,000 um.

In U.S. Pat. No. 4,898,781, a dispersion is formed of enzyme powder inpropylene glycol and aqueous polyvinyl alcohol and this dispersion isthen converted into particles by various techniques. In one technique,the dispersion is introduced as droplets into an aqueous solution ofcross linking agent, thereby solidifying by cross linking the polyvinylalcohol. In another technique, the dispersion is dispersed into ahydrophobic solvent and then heated so as to drive off water andsolidify the polyvinyl alcohol. The products are said to have a size of20 to 1,000 um. Other techniques are described. JP-A-63105098 includessimilar process description and many of the examples are identical. Itproposed that the particles of enzyme in a covering of polyvinyl alcoholshould be homogeneously dispersed in a liquid or gel detergent.

EP-A-356,240 (and U.S. Pat. No. 5,035,900) describes processes forencapsulating enzyme or other biologically produced material in a matrixof polymeric material by mixing the polymeric material with an aqueousliquor containing the biologically produced material (as a fermentationliquor or plant extract), dispersing this mixture in a water immiscibleliquid and azeotroping the dispersion. The product can either berelatively coarse beads that can be recovered or a stable dispersion ofsmall particles in the water immiscible liquid. Although this is a veryuseful recovery technique and provides some protection to the enzyme,additional stabilisation is desirable.

In EP-A-356,239 (which is equivalent to part of the disclosure in U.S.application Ser. No. 734,545, now U.S. Pat. No. 5,324,445 of 23rd Jul.1991) we have described various compositions and processes primarilyintended for the encapsulation of enzymes for liquid and otherdetergents. One type of product described therein comprises particleshaving a core comprising matrix polymer containing the enzyme, oilaround the core and a polymer shell around the oil.

In particular, particles of a matrix polymer containing an activeingredient can be formed as a dispersion in oil and this dispersion canthen be dispersed in an aqueous solution of an encapsulating polymer orblend of polymers and polymer deposition can then be caused to occuraround the oil particles that contain the particles of matrix polymerthat contain the active ingredient.

As explained in EP 356,239, it can be desirable for the matrix polymerto be a salt formed between ammonia or other volatile amine and apolymer derived from ethylenically unsaturated carboxylic acid. Thematrix polymer can be formed or introduced as an aqueous solution of thesalt with a volatile amine and this dispersion can then be subjected toazeotroping to drive off water and the volatile amine, so as to solidifythe polymer wholly or partially in the free acid form. The solid polymerwill be less hydrophilic than the starting amine salt and so willprovide some impermeability to protect the encapsulated enzyme frommoisture. The combination of this relatively impermeable matrix, theouter polymer shell, and the intervening oil would be expected toprovide excellent stability to the enzyme. Although the system does givesignificant improvements, there is still some loss of activity.

It would be desirable to be able to provide coacervated particles thatcould more reliably protect any active ingredient in the matrix fromexposure to moisture during manufacture and subsequent storage.

A particulate composition according to the invention comprises particleshaving

a substantially anhydrous core comprising one or more particles of amatrix polymer containing active ingredient and

a layer of hydrophobic oil around the matrix polymer particle orparticles, and

a shell of polymer around the oil layer,

wherein the solid matrix polymer is sufficiently hydrophobic that itwill partition preferentially into the oil rather than into water.

By referring to partitioning into "water", we are referring inparticular to the partitioning of the solid matrix polymer into theaqueous solution from which the shell polymer was formed. In manyinstances, the partitioning properties into ordinary water do, however,give a useful guide.

If the encapsulating polymer was deposited from a neutral solution, thenit is more convenient to define the matrix polymer as partitioning intothe oil in preference to water, but if the encapsulating polymer wasmixed with the dispersion in the form of an alkaline solution then therelative partitioning effect should be determined with respect to analkaline solution corresponding to the alkalinity of that solution inorder to allow for any solubilisation of the polymer by salt formationwith the alkali of the encapsulating solution.

A process according to the invention for producing encapsulatedparticles comprises

providing an aqueous solution of encapsulating polymeric material thatcan be caused to deposit as a solid shell about particles dispersed inthe solution,

providing a substantially anhydrous dispersion in oil of particles of amatrix polymer containing active ingredient,

dispersing this substantially anhydrous dispersion of matrix polymerparticles containing active ingredient in oil into the aqueous solution,and causing a solid polymer shell to form around droplets of the matrixparticles in oil, wherein the matrix polymer partitions into the oil inpreference to the aqueous solution of encapsulating polymeric material.

The invention is based on our realisation that, even though the matrixpolymer in EP 356,239 was relatively non-hydrophobic, it wasconsiderably more hydrophilic than the oil with the result that theaqueous solution of encapsulating polymer and the matrix polymerparticles were attracted to one another with undesirable consequences.Since the formation of the dispersion generally involved homogenisingthe polymer-in-oil dispersion into the aqueous solution encapsulatingpolymer, the act of forming the dispersion was able to result inintimate and prolonged contact between the polymer particles and theaqueous solution.

It seems that during this contact there can be migration of water fromthe solution into the matrix polymer, with the result that, even thoughthe polymer particles had been dried by azeotroping, the particles thatwere then encapsulated within the outer shell contained trappedmoisture. This can be undesirable for enzymes and other activeingredients.

Also, there can be some migration of the enzyme or active ingredient outof the matrix polymer and into the aqueous solution, thereby losing thebenefit of trapping the enzyme initially in the matrix polymer.

Finally, because of the attraction of the aqueous solution to the matrixpolymer, the encapsulating polymer could tend to deposit direct on tothe matrix polymer, without any oil trapped between the matrix polymerparticle and the encapsulating polymer shell. Since the oil is capableof hindering the inward migration of moisture, this also wasundesirable.

In the invention, we use a matrix polymer that is so hydrophobic that itpartitions preferentially into the oil rather than into the aqueoussolution of encapsulating polymer.

This therefore reduces the risk of moisture migrating from the aqueoussolution into the matrix, and it reduces the risk of enzyme or activeingredient migrating out of the matrix into the aqueous solution.Because the aqueous solution is incompatible with both the hydrophobicoil and the matrix polymer there is increased tendency for theencapsulating shell to be formed around a layer of oil, rather than indirect contact with a matrix polymer particle. Finally, the increasedhydrophobic properties of the matrix polymer reduce still further thetendency for migration of moisture into the polymer.

In a preferred process of the invention, the substantially anhydrousdispersion of particles of the matrix polymer in oil is made byproviding a dispersion in oil of an aqueous solution of matrix polymericmaterial containing enzyme or other active ingredient, subjecting thisdispersion to distillation to provide a substantially anhydrousdispersion in oil of particles of matrix polymer containing activeingredient, and during or after the distillation converting the polymersolution into a solid polymer.

The initial aqueous solution of matrix polymeric material can be made bydissolving the polymeric material in water or other aqueous solution inwhich it is soluble, and dispersing or dissolving-the active ingredientin the solution. In another process, the dispersion is made by reversephase polymerisation of a water soluble monomer or monomer blend in thepresence of the active ingredient.

The conversion of the droplets of polymer solution into solid polymerparticles can be brought about by various techniques. For instance, itcan be due merely to evaporation of solvent. It can be due to chemicalmodification even though solidification may include another cause. Thismodification should produce a polymer that is insoluble in water andthat will partition into the oil in preference to the aqueous solutionof encapsulating material.

One form of chemical modification can involve cross linking, forinstance a cross linking agent can be included in the polymer solutionand will cause cross linking during or after the azeotroping.

Another, and preferred, form of chemical modification comprisesconverting a polymer that is in salt form into free base or free acidform. Thus a polymer containing amino groups can be present initially asa water soluble salt but can be insolubilised by conversion to the freebase, or polymer that is in anionic soluble salt form can beinsolubilised by conversion to the free acid. Such conversion can bepartial or complete. Preferably the salt forming moiety is volatile withthe result that conversion to the free acid or free base can be achievedduring distillation. Amine (including ammonium) salts of anionic polymerare preferred. The modification normally occurs during or afterazeotroping and renders the matrix less permeable, e.g. to liquiddetergent concentrate.

Another way of converting the matrix polymer to solid form is byselecting a hydrophobic polymer from the class known as "low criticalsolution temperature" (LCST) polymers. The process by which these can beused for the matrix is substantially the same as the process by whichthey can be used for forming the encapsulating shell, and this isdescribed in more detail below. In brief, a characteristic of suchpolymers is that they can be insolubilised by heating to a criticaltemperature (for instance as can happen during the distillation stage)and a depressant for the temperature of insolubilisation (for instance awater miscible non-solvent or an electrolyte) can be added to stabilisethe solid form at a lower temperature. This is all described in moredetail below.

Other coacervating techniques can be used.

In this specification, and in particular in the following discussion ofthe formation of the polymer shell, we use the term "coacervation" and"coacervating polymer" in the general sense described above, namely anymechanism by which a polymer can be converted from a solution form to asolid, encapsulating, form. Accordingly, for convenience, we refer belowto the encapsulating polymer as a coacervating polymer and we refer tothe aqueous solution of this as an aqueous coacervating solution.

By saying that the matrix polymer partitions into the oil in preferenceto the aqueous solution of coacervating polymer, or other water phase,we mean that the polymer particles will be preferentially attracted tothe oil phase rather than to the aqueous phase. One simple way ofdemonstrating whether or not the matrix polymer does preferentiallypartition into the oil phase is to incorporate some water soluble dyeinto the matrix polymer and then to disperse vigorously a dispersion ofthe dyed polyer particles in the oil into the aqueous phase, and then toallow the dispersion to phase separate. If substantially all the dye hasremained in the polymer particles, this shows that there wassubstantially no contact between the polymer particles and the water,and that the polymer particles therefore partition preferentially intothe oil phase. However if the water phase is significantly dyed, thisshows that the polymer particles have partitioned significantly orpreferentially into the aqueous phase.

The oil can be any hydrophobic, water immiscible, liquid. Examples arealiphatic, cycloaliphatic, aromatic and naphthenic oils, vegetable oilsand silicone oils.

Because the oil is hydrophobic, and because the matrix polymer also ishydrophobic and is attracted to the oil in preference to the water, afilm or larger amount of oil is held around each polymer particle duringthe formation of the coacervate, and the coacervate coating is formed asan outer shell around this inner shell of oil. This has two significantadvantages:

Firstly, there is little or no direct contact between the aqueouscoacervating phase and the substantially anhydrous matrix polymer. As aresult, there is little or no opportunity for water to migrate into thesubstantially anhydrous matrix polymer during the formation of thecoacervate coating or for active ingredient in the matrix polymer tomigrate out into the coacervating solution. In particular, thecoacervation can be conducted without raising the moisture content ofthe matrix polymer.

Secondly, the active ingredient in the matrix polymer is protected fromits surroundings not only by the outer coacervate coating but also bythe inner layer of hydrophobic oil. Thus even if the coacervate coatinghas a tendency to allow permeation by moisture, the inner shell ofhydrophobic oil between the coacervate and the matrix polymer willreduce or eliminate any risk of transfer of moisture from outside theparticle to the matrix polymer or transfer of water soluble activeingredient in the matrix polymer to outside the coacervate coating.

In order that the polymer does partition preferentially into oil, it isnecessary for it to be much more hydrophobic than, for instance, theacrylic acid-ammonium acrylate polymer proposed in EP 356239.

As mentioned above, the matrix polymer is generally provided byinsolubilising a polymer that was initially provided as an aqueoussolution. Any modification that achieves this insolubilisation can beused but preferably the modification is reversible so that the polymercan then be solubilised when it becomes necessary to facilitate releaseof active ingredient from within the particles into water. Themodification can be achieved chemically or physically. When themodification is achieved chemically, the initially soluble polymer ispreferably a copolymer of water soluble ionic monomer with waterinsoluble monomer, in which event the reversible insolubilisation willpreferably comprise converting some or all of the ionic monomer groupsto free acid or free base monomer groups.

Suitable monomers are ethylenically unsaturated monomers. Ionic monomersare preferably anionic monomers groups that include sulphonic or,preferably, carboxylic acid groups. Preferred monomers includemethacrylic and acrylic acids. The anionic groups may be present in thesoluble polymer as alkali metal or amine salts and may be converted tofree carboxylic acid groups in the insolubilisation reaction. This canbe achieved by acidification with hydrochloric acid or other suitableacid but preferably the anionic group is present as a salt of a volatileamine (e.g., ammonia) and the acidification is achieved by heating thepolymer sufficient to volatilise the ammonia or other amine. Thisheating can occur during the distillation step. Although anionic groupsare preferred as the ionic groups, cationic groups such asdialkylaminoalkyl (meth)-acrylate or amide acid addition or quaternaryammonium salt can be used.

The ionic groups must be copolymerised with hydrophobic water insolublemonomer. Suitable hydrophobic ethylenically unsaturated monomers arehydrocarbon monomers such as styrene and alkyl-substituted styrenes,alkyl acrylates and methacrylates (for instance methacrylate) and vinylacetate.

The amount of hydrophobic monomer will generally be from 40 to 95% byweight, with the balance to 100% being the ionic monomer. However smallamounts (e.g., up to 20%) of other monomers that are neither ionic norhydrophobic may be included, an example being vinyl pyrrolidine.

The matrix polymeric material can be made by solution polymerisation inthe organic solvent or by oil-in-water emulsion polymerisation, followedby addition of sufficient alkali to solubilise the aqueous polymer inthe conventional manner. Active ingredient can be dispersed or dissolvedin the polymerising mixture before polymerisation, but preferably isdispersed or dissolved into a solution of the polymeric material afterpolymerisation. The polymer can be made as a water soluble salt byreverse phase polymerisation, e.g., in the hydrophobic oil that is usedin the encapsulation process.

If the polymer was not formed as a reverse phase emulsion, the resultantsolution of polymer containing active ingredient can be dispersed intothe desired hydrophobic oil (or the polymer can be dispersed in the oiland the active ingredient then added) in the presence of suitabledispersion stabiliser that can be a water-in-oil emulsifier and/or anamphipathic polymeric stabiliser. Suitable emulsifiers, stabilisers andoils are described in, for instance, EP 128,661, EP 284,366 and EP284,367. Emulsification can be achieved by homogenisation with aSilverson or other homogeniser.

The dispersion of aqueous polymer and active ingredient in oil cansubsequently be subjected to distillation under reduced pressure untilsubstantially all the water has been removed. If the active ingredientis temperature sensitive, the reduced pressure should be sufficientlylow that the distillation occurs at a safe temperature, for instancebelow 30° C. Anionic monomer is preferably present as ammonium salt, inwhich event the dispersion can be heated briefly to a temperature andfor a time sufficient to drive off most of the ammonia but insufficientto damage any heat-sensitive active ingredient in the matrix polymer.

The resultant dispersion of dry polymer particles in oil can then bedispersed into an aqueous solution of coacervating polymeric material,for instance by emulsification using a Silverson homogeniser. Theparticle size can be controlled in known manner by appropriate selectionof the emulsification conditions and generally is below 20 μm, usuallybelow 10 μm, although if desired the process can be used to make largerparticles, e.g., up to 100 um or 500 um. The size will usually be above0.3 μm, e.g. up to 3 μm

If the particle size of the resultant oil-in-water dispersion is small,each oil droplet may only contain one particle of matrix polymer, withthe result that the core of the final product comprises a single matrixpolymer particle surrounded by some oil. However each droplet, andtherefore each core, often includes several matrix polymer particlesdispersed in oil.

Coacervation can be by any known technique, for instance any of thosementioned or used in EP 356,239, but is preferably by use of "lowcritical solution temperature" (LCST) polymers. Coacervation can bebrought about solely by heating as described in U.S. Pat. No. 3,244,640but preferably coacervation is brought about by heating followed by theaddition of a depressant. In particular, a process for encapsulating bycoacervation particles each comprising matrix polymer (containing activeingredient) and an outer layer of oil can be performed as described inour Application filed today Ser. No. 08/196,230, now abandoned thatclaims priority from British Application 9110407.5. This processcomprises

providing an aqueous solution of a LCST polymer that has a temperatureof reversible insolubilisation (TRI) in that solution of T1,

forming a dispersion of the particles in that solution at a temperatureT2 that is below T1,

heating the dispersion to a temperature above T1 and therebyprecipitating the LCST polymer as a coascervate around the particles,then

adding a TRI depressant to the solution and thereby reducing thetemperature of reversible insolubilisation of the LCST polymer in thatsolution to a temperature T3 that is lower than T1, and

either cooling the dispersion to a temperature between T3 and T1 andmaintaining the dispersion at a temperature between T3 and T1,

or separating the particles from the dispersion while at a temperatureabove T3.

The TRI depressant, and its amount, are selected to give the desireddepression in the temperature of reversible insolubilisation. Preferablyit is an electrolyte.

A wide variety of electrolytes can be used but since satisfactoryresults are obtained with simple inorganic salts, it is generallypreferred to use them as part or all of the electrolyte. Suitable saltsinclude sodium, potassium, ammonium, calcium, magnesium and aluminiumsalts, particularly of carbonate, sulphate, chloride and nitrate. Someor all of the electrolyte can be anionic surfactant, for instance of thetype conventionally present in a liquid detergent concentrate.

Typical amounts of salt that should be added are 2 to 30% based on theaqueous composition, or such as to give a 15:1 to 1:15 weight ratio ofpolymer:salt. The amount is preferably sufficient for T3 to be at least5° C. below the anticipated lowest temperature of storage. As mentioned,some electrolyte can be present in the initial solution, typically in anamount of 0 to 5% based on the initial solution, provided this does notdepress T1 too much.

Generally T1 is at least 5° C. higher than the anticipated temperatureof usage, for instance the temperature of the dilution water into whichthe particles are to be dissolved.

Although we prefer to use an electrolyte for depressing the reversibleinsolubilisation temperature, any other material that has the desireddepressant effect can be used. Generally they can all be characterisedas being water-miscible non-solvents (in the absence of significantamounts of water) for the relevant LCST polymer. Examples includeorganic liquids such as lower alcohols, glycols and non-ionicsurfactants. Particular examples are ethanol, glycerol, ethylene glycol,mono propylene glycol and ethoxylated octyl or nonyl phenol surfactants.

The LCST polymer can be a naturally occurring polymer such as certaincellulose derivatives, such as the methyl, hydroxy propyl, and mixedmethyl/hydroxy propyl cellulose ethers. However it is generallypreferred for the LCST polymer to be a synthetic polymer formed bypolymerisation of what can be termed an LCST monomer either as ahomopolymer or as a copolymer with a hydrophilic monomer that is presentin an amount insufficient to cause T1 to be unacceptably high. SuitableLCST monomers include N-alkylacrylamide, N,N-dialkylacrylamide,diacetone acrylamide, N-acryloylpyrrolidine, vinyl acetate, certain(meth) acrylate esters (especially hydroxypropyl esters), styrene, andvarious other vinyl monomers, especially N-vinylimidazoline and thelike.

When the LCST polymer is a copolymer, the comonomer is usuallyhydrophilic and can be non-ionic or ionic. Suitable non-ionic monomersinclude acrylamide, hydroxyethyl acrylate, vinyl pyrollidone, orhydrolysed vinyl acetate.

Anionic or cationic monomer can be used in place of or in addition tothe non-ionic comonomer to form a copolymer or terpolymer with the LCSTmonomer respectively. Suitable anionic monomers include ethylenicallyunsaturated carboxylic or sulphonic acid monomers, for example (meth)acrylic acid and alkaline salts thereof, and 2-acrylamido methyl propanesulphonic acid. Suitable cationic monomers include dialkylaminoalkyl(meth)acrylates and acrylamides as acid addition or quaternary ammoniumsalts, for example dialkylaminoethyl (meth)acrylate acid addition salts.One beneficial effect resulting from the use of cationic or anioniccomonomer or termonomer is that their presence can prevent thecoagulation and subsequent phase separation of the encapsulatedparticles which may occur in particularly high salt environments such asmay exist in certain detergents.

The method relies upon the reversible insolubilisation by temperaturechange of an LCST polymer to form a coacervate coating, followed by theaddition of a TRI depressant to modify the properties of the coating ina beneficial manner. Since the initial insolubilisation is bytemperature change, this can be conducted homogeneously througout thecomposition and so can yield very uniform coacervation.

An essential modification of the coating is that the TRI depressantreduces the temperature of reversible insolubilisation of the coating.This means that the temperature of the solution can be cooled below thetemperature at which the coacervate coating was first formed without thecoating being solubilised. This permits handling, storage and recoveryat ambient temperatures.

Another modification is that the addition of the TRI depressant can tendto change other physical properties of the coating of the LCST polymer.In particular, it is easily possible to select an LCST polymer thatforms a much harder and less permeable coating in the presence of anadded electrolyte (as the TRI depressant) than in its absence. Thus theaddition of the electrolyte will generally both reduce the temperatureof reversible insolubilisation of the polymer and will render thecoating much harder and less permeable than it would be in the absenceof the electrolyte.

However, the effect is reversible since when the concentration of TRIdepressant is sufficiently reduced, the temperature of reversibleinsolubilisation will then rise again to, or at least towards, theinitial temperature T1 of reversible insolubilisation. Also, if the TRIdepressant hardened the coating, the coating may tend to revert to itsoriginal softer and more permeable texture.

The temperature T1 of reversible insolubilisation of the LCST polymer isthe temperature at which the polymer will become insoluble if thesolution containing the polymer is heated past T1 or will become solubleif insoluble polymer in that aqueous solution is cooled below thattemperature. The temperature of reversible insolubilisation is generallyreasonably abrupt, but may extend over a few degrees or more. NaturallyT3 must be sufficiently low that any range for T1 does not significantlyoverlap the range for T3, which is the corresponding temperature for thepolymer in the aqueous solution containing the TRI depressant. It shouldbe noted that T1 and T3 relate to the polymer in the particular aqueoussolution in which it exists. Thus, in the invention, the initial aqueoussolution can contain some electrolyte or other TRI depressant in whichevent T1 in that solution will generally be lower than it would be ifthe initial solution had been free of electrolyte or other depressant,but additional electrolyte or other depressant is then added to reducethe temperature of reversible insolubilisation to T3.

T1 is generally at least 25° C. and often at least 30° C. and frequentlyis in the range 45° to 80° C. but can be as high as 100° C. Somepolymers require the presence of some electrolyte in order to bring T1in the initial solution down to a convenient value, e.g. below 100° C.

T3 is generally at least 5° C. lower than T1 and is preferably at least10° C. and often at least 20° C. below T1. When the particles are to bestored in aqueous electrolyte, T3 should be below the probable storagetemperature. Preferably T3 is 0° C., that is to say the coating willnever dissolve in liquid water, but higher values of T3, such as 5° C.or even 10° C., can be acceptable in many instances.

Irrespective of how the coacervation of the shell is achieved, thechoice of coacervate shell must be such as to allow eventual release ofactive ingredient from within the matrix when the product is exposed toselected conditions, whilst preventing release prior to that stage. Forinstance, if the particles are in the form of dry powder the coacervateshell should reduce ingress of ambient moisture sufficient to preventsignificant deactivation of the active ingredient but upon exposure todilution water or an appropriate chemical reagent (for instance dilutealkali), the shell should permit adequate permeation through the shelland from the matrix into the surrounding liquor.

When the composition is in the form of a dispersion in liquid, the shellshould prevent permeation of that liquid through the shell but should becapable of permitting permeation when the liquid is changed, forinstance when it is diluted. When, as is preferred, the composition isin the form of a liquid detergent in which the encapsulated particlesare dispersed, the shell should be such as to prevent substantiallypermeation of the alkaline liquid through the shell but should be suchas to permit permeation by wash water, often warm wash water, when theliquid detergent is diluted in wash water.

Suitable coacervating polymers can be the LCST polymers mentioned aboveand the coacervating polymers that have previously been proposed for,for instance, the coacervate shell around enzyme particles, especiallyenzyme particles that are to be dispersed into a liquid detergent.Suitable materials are described in, inter alia, EP-A-356239. Crosslinked pva is suitable.

A wide variety of active ingredients can be encapsulated by thedescribed technique including dyes (for pressure sensitive paper),agricultural chemicals, perfumes, flavours, condiments, essential oils,bath oils, bleaching agents, and enzymes. Suitable agriculturalchemicals are water insoluble pesticides (e.g. herbicides andinsecticides) that would otherwise need to be formulated as, forinstance, an emulsifiable solution in oil. The invention is ofparticular value when applied to the encapsulation of enzymes, and inparticular detergent enzymes, i.e. enzymes of the type that are usefulfor inclusion in laundry or other detergent compositions.

When the particle size is small, e.g. below 20 um, the particulatecomposition is generally provided as a dispersion in the liquid medium,for instance a liquid detergent. When the particle size is larger, forinstance above 50 um and especially above 100 um, the particles can berecovered as dry particles.

The liquid or dry composition can be substantially storage stable due tothe protection provided by the matrix polymer, the oil layer and theencapsulating coacervate shell. Upon mixing with water, or otherappropriate change in the ambient conditions, the outer shelldisintegrates or swells sufficient to allow penetration of the oil layerand release of the active ingredient from within the matrix, possiblyafter chemical reversion of that matrix to render it more hydrophilic.For instance, if, as is preferred, the matrix polymer is the acid formof an anionic polymer, exposure to alkaline wash water will tend tosolubilise it.

Suitable proportions of active ingredient: matrix polymer are 1:100 to1:0.5 on a dry weight basis, whilst the matrix/activeingredient:coacervate polymer ratio is generally from 1:60 to 5:1 on adry weight basis. The amount of oil encapsulated within the particles isgenerally from 20 to 97% based on the dry weight of the particles.

When the active ingredient is an enzyme for detergents and thecomposition is a liquid detergent, its formulation can be conventionalfor enzyme-containing liquid detergents except that the enzyme isincluded in the form of the described particles. Typical liquiddetergents comprise, in % by weight,

    ______________________________________                                        Component           Soap Built                                                                              Citrate Built                                   ______________________________________                                        Linear alkyl benzene sulphonate                                                                   10        10                                              Alkyl ether sulphate                                                                               2         4                                              Soap                14         1                                              Alcohol ethoxylate  13         6                                              Sodium hydroxide (Triethanolamine)                                                                 2(5)      1(0)                                           Sodium xylene sulphonate                                                                           1         5                                              Sodium sulphate      0         1                                              Sodium carbonate     0         2                                              Tri-sodium citrate   1         6                                              Ethanol              5         1                                              Monopropylene glycol                                                                               3         3                                              Water               44        60                                              ______________________________________                                    

EXAMPLE 1

Preparation of LCST copolymer

Diacetone acrylamide (1 part) and acrylamide (0.4 part) were dissolvedin 1% aqueous sodium acetate at pH 6.5 (4.2 parts). This solution waspurged with nitrogen for 45 min in a lagged reaction vessel fitted witha mechanical stirrer.

Polymerisation was initiated by addition of 5% aqueous ammoniumpersulphate (500 ppm) followed by 5% aqueous sodium metabisulphite (500ppm). The course of the reaction was monitored by recording thetemperature. After 30 min, the temperature had risen from 20° C. to aconstant value of 70° C.

The mixture had become white and opaque and more viscous. On cooling, apale yellow clear viscous solution (25%) of Polymer A resulted.

By measuring the onset of turbidity of a 10% aqueous solution of PolymerA, the lower critical solution temperature (or temperature of reversibleinsolubilisation), was found to be 30° C.

EXAMPLE 2

Savinase plus matrix polymer dispersion in oil

An aqueous phase is formed by mixing 160 g 30% solution of a copolymerof styrene and ammonium acrylate with 140 g liquid Savinase preparation(12 g active protease enzyme, supplied by Novo-Nordisk A/S) and its pHis adjusted to 9.0).

The oil phase is formed by mixing 9 g polymeric inverse emulsifier, 12.7g 60% amphipathic polymeric stabiliser, 107.9 g non-volatile hydrocarbonoil and 31.9 g volatile hydrocarbon solvent.

The aqueous phase is added to the agitated oil phase and thenhomogenised with a high shear Silverson mixer whilst maintaining thetemperature of the emulsion below 40° C. After 30 minutesemulsification, extra 138.5 g of the volatile hydrocarbon solvent isadded as a diluent.

The resultant emulsion is warmed to 30° C. and water/solvent mixturedistilled under reduced pressure at a constant temperature about 30° C.The volume of water and solvent removed is monitored and distillationcontinued until no further water is collected in the distillate and thenthe temperature is allowed to rise to 110° C. under vacuum to removeremaining solvent. The dried dispersion is held at 100° C. for 15minutes to drive off ammonia so as to render the matrix polymerinsoluble in water.

The contents of the flask are cooled. The dispersion of Savinase pluspolymer particles in oil (40% solids) is stable and having an averageparticle diameter of less than 1 μm.

EXAMPLE 3

Microencapsulation of dispersion-in-oil obtained in Example 1

The dried enzyme/polymer dispersion (33 parts) from Example 1 is addedwith high shear mixing to 100 parts 10% solution of Polymer A at pH 4from Example 1.

The resultant smooth o/w emulsion is warmed in a water bath to 40° C.and held at this temperature for 15 min. Aqueous sodium sulphate (10%, 5parts) is added and the mixture then allowed to cool slowly to 20° C. Astable microcapsule suspension in water is obtained having averageparticle size diameter of about 1 micron.

EXAMPLE 4

The Savinase dispersion in oil prepared as in Example 2 (40 parts) wasmixed with gentle agitation into 400 parts of an aqueous solution ofpoly-(vinyl alcohol) (2%; 74% hydrolysed; M_(n) 25000) adjusted to pH4with dilute hydrochloric acid.

This mixture of oily droplets (containing the dispersed particles ofhydrophobised enzyme) was warmed to 42° C. over 15 mins and held at thistemperature for a further 30 mins. The outer shell of coacervatedpoly-(vinyl alcohol) which could be seen clearly under the microscope tosurround the oil droplets (average particle size 300 micron) wascross-linked by addition of 1 part of 50% aqueous glutaraldehydesolution, pH adjusted to 3 by a few drops of concentrated hydrochloricacid and the mixture stirred gently for 5 h at 42° C.

The capsules produced by this method were recovered by sieving through afine nylon mesh were physically strong and could be recovered in a dryform by aerial drying. An enzyme assay for protease activity afterphysical rupture of these capsules in dilute aqueous detergent at pH9showed 88% of the protease activity present in the oil proteasesuspension from Example 2.

A modern heavy duty compact powder detergent was formulated. To one halfof this powder detergent was added the capsules-containing Savinase asdescribed above. Savinase 6.0T granules (Novo-Norsik A/S Denmark) wereadded to the other half of the powder detergent to give an equalprotease activity.

Both enzyme containing formulations were subjected to an acceleratedstorage stability test by being placed in open jars at 37° C. and 70%relative humidity. Protease assays of both formulations showed there tobe more than double the activity in the capsules formulation than in theone made with normal granulated Savinase 6.0T.

EXAMPLE 5

The process of Example 4 was repeated but to a smaller particle size andthe microcapsules containing the Savinase were added to a soap builtliquid detergent and accelerated storage stability tests performed at30° C. compared with a control which contained unprotected Savinase atthe same protease activity. After 15 days, the capsule containing liquiddetergent contained 2.5 times the protease activity than the unprotectedcontrol.

EXAMPLE 6

Demonstration of partitioning and dissolution characteristics

Using the azeotropic distillation process as described in Examples 1 and2, a dispersion comprising a dispersed phase of a styrene/acrlic acidpolymer in a paraffinic oil is prepared. A water soluble polymeric dye(blue dextran) is incorporated into the polymer particles at 0.5% wt asa marker.

An experiment is performed to see if the polymer particles wouldactivate (i.e. partition into and dissolve in the aqueous phase) oncontact of matrix polymer plus dye dispersion with water at twodifferent pH values.

The dispersion (1 part) was added with high shear mixing to water (99parts) at either pH4 or pH9. After 2 min mixing, the turbid mixture wascentrifuged with these results:

    ______________________________________                                        pH       Observation       Conclusion                                         ______________________________________                                        4        Blue colour associated                                                                          No activation                                               with oily layer                                                               Solution clear                                                                colourless                                                           9        Distinct blue solution                                                                          Activation                                                  with a trace of oil                                                           on surface                                                           ______________________________________                                    

Therefore it can be seen that under acidic conditions the matrix polymerremains water insoluble and the particles stay in the oil phase. Thusthe polymer particles are considered to partition into the oil phase atpH4, which is the pH4 prevailing at the time the dry polymer-in-oildispersion is mixed into the aqueous coacervating solution. However whenexposed to dilute alkali at pH9 (e.g. as would apply after permeation ofthe coacervate shell in dilute laundry wash water) the matrix polymerdissolves and releases its active ingredient.

We claim:
 1. A particulate composition comprising particles having asubstantially anhydrous core comprising one or more particles of amatrix polymer containing active ingredient and a layer of hydrophobicoil around the matrix polymer particle or particles, and a coacervateshell around the oil layer formed by coacervation of coacervate polymerwherein the solid matrix polymer is sufficiently hydrophobic that itwill partition preferentially into the oil rather than into water.
 2. Aprocess for producing encapsulated particles comprising selecting amatrix polymer, providing a dispersion in oil of an aqueous solution ofthe matrix polymer containing active ingredient, subjecting thisdispersion to distillation to provide a substantially anhydrousdispersion in oil of particles of matrix polymer containing activeingredient and during or after the distillation converting the matrixpolymer into a solid polymer, providing an aqueous solution ofencapsulating polymeric material that can be caused to deposit as asolid shell about particles dispersed in the solution, dispersing thesubstantially anhydrous dispersion of matrix polymer particlescontaining active ingredient in oil into the aqueous solution andcausing a solid coacervate polymer shell to form around droplets of thematrix particles in oil, wherein the polymer which is selected as matrixpolymer is a polymer which partitions into the oil in preference to theaqueous solution of encapsulating polymeric material.
 3. A processaccording to claim 2 in which the matrix polymer is an ionic polymerwhich is soluble in water when present in salt form but is insolublewhen in free base form or free acid form, and in which the conversion ofthe matrix polymer into a solid polymer is achieved by converting thesoluble salt into the insoluble free acid or free base polymer.
 4. Acomposition according to claim 1 in which the coacervate shell ofpolymer is cross linked.
 5. A composition according to claim 1 in whichthe coacervate shell of polymer is formed of polyvinyl alcohol.
 6. Acomposition according to claim 1 in the form of dry particles having asize above 50 um.
 7. A composition according to claim 1 that is a liquidcomposition comprising a substantially stable dispersion in a liquid ofthe particles.
 8. A composition according to claim 7 which is a liquiddetergent concentrate wherein the active ingredient is an enzyme usefulin detergents.
 9. A composition according to claim 7 in which theparticles are below 20 um in size.
 10. A process according to claim 3 inwhich the matrix polymer is formed by polymerisation of ethylenicallyunsaturated monomers comprising water soluble ionic monomer and waterinsoluble hydrophobic monomer.
 11. A process according to claim 3 inwhich the solid matrix polymer is a copolymer of hydrophobic monomerwith anionic monomer in substantially free acid form.
 12. A process forproducing encapsulated particles comprising selecting a matrix polymer,providing an aqueous solution of encapsulating polymeric material thatcan be caused to deposit as a solid shell about particles dispersed inthe solution, providing a substantially anhydrous dispersion in oil ofparticles of the matrix polymer containing active ingredient, dispersingthis substantially anhydrous dispersion of matrix polymer particlescontaining active ingredient in oil into the aqueous solution, andcausing a solid coacervate polymer shell to form around droplets of thematrix particles in oil, and in which the selected matrix polymerpartitions into the oil in preference to the aqueous solution ofencapsulating polymeric material.
 13. A process according to claim 12 inwhich the encapsulated particles are combined with a liquid to form asubstantially stable dispersion of the particles in the liquid.
 14. Aprocess according to claim 2 in which the solution of matrix polymer isa solution of an anionic polymer in the form of a salt with a volatileamine, and the amine is evaporated during or after the distillation. 15.A process according to claim 2 in which the formation of the solidpolymer shell comprises the cross linking of polyvinyl alcohol.
 16. Anencapsulated particle made by the process of claim
 12. 17. A processaccording to claim 2 in which the causing a solid coacervate polymershell to form comprises crosslinking polymer.
 18. A process according toclaim 2 in which the coacervate polymer is polyvinyl alcohol.
 19. Aprocess according to claim 2 in which the coacervate particles are dryand have a size above 50 μm.
 20. A process according to claim 13 inwhich the liquid composition is a liquid detergent.
 21. A processaccording to claim 13 in which the active ingredient is an enzyme usefulin detergents.
 22. A process according to claim 13 in which theparticles are below 20 μm in size.
 23. A process according to claim 2 inwhich the encapsulated particles are combined with a liquid to form asubstantially stable dispersion of the particles in the liquid.
 24. Aprocess according to claim 23 in which the liquid composition is aliquid detergent.
 25. A process according to claim 23 in which theactive ingredient is an enzyme useful in detergents.
 26. A processaccording to claim 23 in which the particles are below 20 μm in size.27. An encapsulated particle made by the process of claim 2.